This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds of the invention are potent and selective inhibitors of type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (cGMP PDE5) and have utility therefore in a variety of therapeutic areas.
In particular, the compounds are of value in the treatment of male erectile dysfunction (MED) and female sexual dysfunction (FSD) but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
WO-A-94/28902 and WO-A-96/16644 relate to the use of various series of cGMP PDE inhibitors for the treatment of MED including, within the latter, the compounds disclosed in EP-A-020188 which are also adenosine receptor antagonists and reported to be useful in the treatment of cardiovascular disorders as well as the compounds disclosed in EP-A-0352960 which have bronchodilator, vasodilator and anti-allergic properties.
Thus the invention provides compounds of formulae (IA) and (IB): 
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity,
wherein R1 is C1 to C3 alkyl substituted with C3 to C6 cycloalkyl, CONR5R6 or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R9-piperazinyl; (CH2)nHet or (CH2)nAr;
R2 is C1 to C6 alkyl;
R3 is C1 to C6 alkyl optionally substituted with C1-C4 alkoxy;
R4 is SO2NR7R8;
R5 and R6 are each independently selected from H and C1 to C4 alkyl optionally substituted with C1 to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R9-piperazinyl group;
R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group;
R9 is C1 to C4 alkyl;,
R10 is H or C1 to C4 alkyl optionally substituted with OH, C1 to C4 alkoxy or CONH2;
Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C1 to C4 alkyl optionally substituted with C1 to C4 alkoxy, C1 to C4 alkoxy, halo and NH2,
Ar is phenyl optionally substituted with one or two substituents selected from C1 to C4 alkyl, C1 to C4 alkoxy, halo, CN, CONH2, NO2, NH2, NHSO2 (C1 to C4 alkyl) and SO2NH2;
and n is 0 or 1.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.
The compounds of formulae (IA) and (IB) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formulae (IA) and (IB) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (IA) or (IB) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (IA) or (IB) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.
The compounds of formulae (IA) and (IB) may also exist in tautomeric forms and the invention includes both mixtures thereof and the individual tautomers.
Also included in the invention are radiolabelled derivatives of compounds of formulae (IA) and (IB) which are suitable for biological studies.
The pharmaceutically or veterinarily acceptable salts of the compounds of formulae (IA) and (IB) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. Compounds of formulae (IA) and (IB) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts.
A preferred salt is the citrate.
A preferred group of compounds of formulae (IA) and (IB) is that wherein R1 is C1 to C2 alkyl substituted with C3 to C5 cycloalkyl, CONR5R6 or a N-linked heterocyclic group selected from pyrazolyl, triazolyl, morpholinyl and 4-R9-piperazinyl; (CH2)nHet or (CH2)nAr; R5 is H and R6 is C1 to C4 alkyl optionally substituted with C1 to C4 alkoxy or R5 and R6, together with the nitrogen atom to which they are attached, form a morpholinyl group; Het is selected from pyridinyl, 1-oxidopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoxazolyl, triazolyl, triazolyl and oxadiazolyl, any of which is optionally substituted with one or two substituents selected from CH3, CH2CH2OCH3, OCH3 and NH2; and R2, R3, R4, R9, Ar and n are as previously defined.
A more preferred group of compounds of formulae (IA) and (IB) is that wherein R1 is C1 to C2 alkyl substituted with cyclobutyl, CONR5R6, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl; pyrimidin-2-yl; CH2Het or (CH2)nAr; R2 is C1 to C3 alkyl; R3 is C1 to C3 alkyl optionally substituted with C1 to C2 alkoxy; R5 is H and R6 is C1 to C2 alkyl optionally substituted with C1 to C2 alkoxy or R5 and R6, together with the nitrogen atom to which they are attached, form a morpholin-4-yl group; R10 is C1 to C2 alkyl optionally monosubstituted with OH, OCH3 or CONH2; Het is selected from pyridin-2-yl, 1-oxidopyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-methylthiazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl, 4-methyl-1,2,4-triazol-3-yl, 3-methyl-1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 4-chlorophenyl, 4-bromophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-carbamoylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl, 4-(prop-2-ylsulphonamido)phenyl and 4-sulphamoylphenyl; and n is as previously defined.
A particularly preferred group of compounds of formulae (IA) and (IB) is that wherein R1 is cyclobutylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl)ethyl, pyrimidin-2-yl, CH2Het or (CH2)nAr; R2 is CH2CH3 or CH2CH2CH3; R3 is CH2CH3, CH2CH2CH3 or CH2CH2OCH3; R10 is CH3, CH2CH3 or CH2CH2OH; Het is selected from pyridin-2-yl, pyridazin-3-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 2-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl and 4-(prop-2-ylsulphonamido)phenyl; and n is as previously defined.
Especially preferred individual compounds of the invention include
5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-1-(pyridin-2-yl)methyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
1-(1-methylimidazol-2-yl)methyl-5-[5-(4-methylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-{5-[4-(2-hydroxyethyl)piperazin-1-ylsulphonyl]-2-n-propoxyphenyl}-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyridazin-3-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;
5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-2-(pyrazin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; and
5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)phenyl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
In a further aspect, the present invention provides processes for the preparation of compounds of formulae (IA) and (IB), their pharmaceutically and veterinarily acceptable salts, and pharmaceutically and veterinarily acceptable solvates of either entity, as illustrated below.
It will be appreciated by persons skilled in the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for use in the said synthetic steps.
Illustrative of protecting group strategies are the routes to the syntheses of Example 56 in which alcohol protection using a t-butyldimethylsilyl group precedes the desired N-mesylation step, Example 63 in which the piperazine 4-position is Boc(t-butoxycarbonyl)-protected to preclude bis-sulphonylation of the piperazine, and Examples 23 and 68 in which amine protection using a pivaloyl group precedes the penultimate chlorosulphonation step.
It will also be appreciated that various standard substituent or functional group interconversions and transformations within certain compounds of formulae (IA) and (IB) will provide other compounds of formulae (IA) and (IB). Examples include alkoxide exchange at the 2-position of the 5-phenyl substituent (see conversion of Example 41 to Example 42), hydrolysis of cyano to carbamoyl (see conversion of Example 46 to Example 47), reduction of nitro to amino (see conversions of Examples 49, 50, 51, 91, 115, 118 and 121 to Examples 52, 53, 54, 93, 116, 119 and 122 respectively), sulphonylation of amino (see conversions of Examples 52, 54, 116, 119 and 122 to Examples 55, 57, 117, 120, and 123 and 124 respectively), hydrogenolysis of halo (see conversion of Example 88 to Example 87) and N-oxidation of pyridinyl (see conversions of Examples 6 and 12 to Examples 128 and 129 respectively).
Moreover, certain compounds of formulae (IA) and (IB) may be prepared directly from the corresponding 4-unsubstituted piperazine analogues, that is compounds of formulae (IA) and (IB) wherein R10 is hydrogen, using standard alkylation procedures.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
1. A compound of formula (IA) or (IB) may be prepared from a compound of formula (IIA) or (IIB) respectively: 
wherein Y is halo, preferably chloro, and R1, R2 and R3 are as previously defined for formulae (IA) and (IB), by reaction with a compound of formula (III):
R7R8NHxe2x80x83xe2x80x83(III)
wherein R7 and R8 are as previously defined for formulae (IA) and (IB).
The reaction is generally conducted at room temperature, preferably in the presence of an appropriate solvent such as a C1 to C3 alkanol, using an excess of (III) or other suitable base to scavenge the acid by-product (HY).
A compound of formula (IIA) or (IIB) may be prepared from a compound of formula (IVA) or (IVB) respectively: 
wherein R1, R2 and R3 are as previously defined for formulae (IIA) and (IIB), by the application of known methods for the introduction of a SO2Y group, wherein Y is also as previously defined for formulae (IIA) and (IIB), into an aromatic ring system. For example, when Y is chloro, by the action of excess chlorosulphonic acid, optionally followed by excess thionyl chloride, at from about 0xc2x0 C. to about room temperature.
A compound of formula (IVA) or (IVB) may be prepared by alkylation of a compound of formula (V): 
wherein R2 and R3 are as previously defined for formulae (IVA) and (IVB), using one or more of a plethora of well-known methods, such as:
(i) reaction of (V) with a compound of formula R1X, wherein R1 is as previously defined for formulae (IVA) and (IVB), and X is a suitable leaving group, e.g. halo (preferably chloro, bromo or iodo), C1-C4 alkanesulphonyloxy, trifluoromethanesulphonyloxy or arylsulphonyloxy (such as benzenesulphonyloxy or p-toluenesulphonyloxy), in the presence of an appropriate base, optionally in the presence of sodium iodide or potassium iodide, at from about xe2x88x9270xc2x0 C. to about 100xc2x0 C. Preferably the alkylation is conducted at from about room temperature to about 80xc2x0 C.
Suitable base-solvent combinations may be selected from
(a) sodium, potassium or cesium carbonate, sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or pyridine, together with a C1 to C4 alkanol, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, acetonitrile, pyridine, dimethylformamide or N,N-dimethylacetamide;
(b) sodium or potassium hydroxide, or a sodium or potassium C1 to C4 alkoxide, together with a C1 to C4 alkanol, water or mixtures thereof;
(c) lithium, sodium or potassium hydride, lithium, sodium or potassium bis(trimethylsilyl)amide, lithium diisopropylamide or butyllithium, together with toluene, ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxan; or
(d) under phase transfer catalysis conditions, a tetraalkylammonium halide or hydroxide, together with a mixture of an aqueous solution of sodium or potassium hydroxide and dichloromethane, 1,2-dichloroethane or chloroform;
(ii) reaction of (V) with a compound of formula R1OH, wherein R1 is as previously defined for formulae (IVA) and (IVB), using classical Mitsunobu methodology. Typical reaction conditions involve treating (V) with the alkanol in the presence of a triarylphosphine and a di(C1 to C4)alkyl azodicarboxylate, in a suitable solvent such as tetrahydrofuran or 1,4-dioxan, at from about xe2x88x925xc2x0 C. to about room temperature.
Certain compounds of formulae (IVA) and (IVB) may be obtained less directly from related analogues, when these are more readily accessible, using the alkylation methods previously described: see, for example, the hydrogenolytic transformation of Preparation 33, wherein R1 is 2,4-dichloropyrimidin-5-ylmethyl, to Preparation 34, wherein R1 is pyrimidin-5-ylmethyl. Similarly, the amides of Preparations 102, 103 and 104 and of Preparations 105, 106 and 107 are obtained from the corresponding carboxylic acids of Preparations 101 and 69 respectively.
Other compounds of formulae (IVA) and (IVB), wherein R1 is CH2Het, may be prepared by construction of the heterocyclic ring subsequent to the pyrazolopyrimidinone-alkylation step. This approach is particularly convenient when the required HetCH2X is relatively inaccessible. For example, when Het is either 3-methyl-1,2,4-triazol-5-yl or 5-methyl-1,2,4-oxadiazol-3-yl, the heterocyclic rings can be assembled from a carboxymethyl precursor and a cyanomethyl precursor respectively, i.e. a compound of formula (IVA) and (IVB) wherein R1 is CH2CO2H or CH2CN, by a series of conventional steps. Each alternative is illustrated by the transformations of Preparation 69 to Preparation 72 and of Preparations 73 and 77 to Preparations 76 and 79.
Yet another variation for obtaining a compound of formula (IVA) or (IVB) is to incorporate the R1 group at a much earlier stage in the synthetic pathway, e.g. by generating a suitably N1- or N2-alkylated pyrazole derivative, which is then processed to (IVA) or (IVB) by analogy with the subsequently described conversion of (VII) to (V).
A compound of formula (V) may be obtained from a compound of formula (VI): 
wherein R2 and R3 are as previously defined for formula (V), by the application of known cyclisation methods for pyrimidinone ring formation. Thus, for example, the cyclisation may be effected by the treatment of (V) with a base such as sodium or potassium hydroxide, or sodium or potassium carbonate, optionally in the presence of hydrogen peroxide, in a C1 to C4 alkanol-water medium at from about 60xc2x0 C. to the reflux temperature of the reaction mixture.
The cyclisation may also be mediated by a sodium or potassium C1 to C5 alkoxide, in a C1 to C5 alkanol as solvent, at from about 60xc2x0 C. to the reflux temperature of the reaction mixture.
Alternative cyclisation procedures include the treatment of (V) with either polyphosphoric acid at from about 130 to about 150xc2x0 C. or with a Lewis acid, e.g. anhydrous zinc chloride at from about 200 to about 220xc2x0 C.
A compound of formula (VI) may be obtained by selective N-acylation of a compound of formula (VII): 
wherein R2 is as previously defined for formula (VI), with a compound of formula (VIII): 
wherein Y is a suitable leaving group, and R3 is as previously defined for formula (VI). For example, when Y is chloro, the reaction may be conducted with the appropriate aroyl chloride in the presence of an excess of a tertiary amine such as triethylamine or pyridine to act as scavenger for the acid by-product (HY), optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at from about 0xc2x0 C. to about room temperature. For convenience, pyridine may also be used as the solvent.
2. An alternative, generally applicable, synthetic route to compounds of formulae (IA) and (IB) involves the incorporation of the R4 substituent at an earlier stage of the synthesis.
Thus a compound of formula (IA) or (IB) may be prepared by cyclisation of a compound of formula (IXA) or (IXB) respectively: 
wherein R1, R2, R3 and R4 are as previously defined for formulae (IA) and (IB). The cyclisation may be effected under basic, neutral or acidic conditions.
Under neutral conditions, a compound of formula (IXA) or (IXB) may be heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or mechanical water-removal system, e.g. a Dean-Stark apparatus. A suitable solvent is 1,2-dichlorobenzene, sulpholane or N-methylpyrrolidin-2-one, a suitable dehydrating agent is molecular sieves and, preferably, the reaction is carried out at from 180 to 220xc2x0 C.
Under acidic conditions, the cyclisation may be carried out by reaction of a compound of formula (IXA) or (IXB) with a protic acid or Lewis acid, optionally in the presence of a solvent. A suitable protic acid is concentrated sulphuric acid, phosphoric acid or p-toluenesulphonic acid, a suitable Lewis acid is boron trifluoride, aluminium chloride, silicon tetrachloride, stannic chloride, titanium tetrachloride, ferric chloride or zinc chloride, a suitable solvent is glacial acetic acid, tetrahydrofuran, 1,4-dioxan or chlorobenzene and, preferably, the reaction is carried out at from 65 to 210xc2x0 C.
However, the preferred mode of cyclisation of a compound of formula (IXA) or (IXB) is under basic conditions, preferably in a solvent, optionally in the presence of hydrogen peroxide or a peroxide salt, and is followed, where necessary, by neutralisation of the reaction mixture. A suitable base is selected from the group consisting of the C1-C12 alkoxide and hydride salts of lithium, sodium and potassium, sodamide, sodium cyclohexylamide and cesium carbonate, the quantity of base employed is from 1.1 to 2.0 molecular equivalents, a suitable solvent is selected from the group consisting of ethanol, n-propanol, t-butanol, t-amyl alcohol, 1-methylcyclohexanol, tetrahydrofuran and 1,4-dioxan, and the reaction is carried out at from 60 to 105xc2x0 C.
Preferably the base is selected from the group consisting of sodium ethoxide, sodium t-butoxide, potassium t-butoxide and sodium hydride; and the solvent is selected from the group consisting of ethanol, n-propanol, t-butanol, t-amyl alcohol and tetrahydrofuran.
A compound of formula (IXA) or (IXB) may be prepared by reaction of a compound of formula (XA) or (XB) respectively: 
wherein R1 and R2 are as previously defined for formulae (IXA) and (IXB) with a compound of formula (XI): 
wherein R3 and R4 are also as previously defined for formulae (IXA) and (IXB).
The coupling reaction may be achieved using conventional amide bond-forming techniques, e.g. via the acyl chloride derivative of (XI), by analogy with the preparation of a compound of formula (VI), ensuring that any potentially vulnerable substituent (for example when R10 is C1 to C4 alkyl substituted with OH or CONH2) is appropriately protected.
In particular, any one of a host of amino acid coupling variations may be used. For example, the acid of formula (XI) may be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole and/or a catalyst such as 4-dimethylaminopyridine, or by using a halotrisaminophosphonium salt such as bromotris(pyrrolidino)phosphonium hexafluorophosphate. Either type of coupling is conducted in a suitable solvent such as dichloromethane, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the compound of formula (XA) or (XB), or the activating reagent, is presented in the form of an acid addition salt), at about 0xc2x0 C. Preferably, from 1.1 to 2.0 molecular equivalents of the activating reagent and from 2.0 to 3.0 molecular equivalents of any tertiary amine present are employed.
Preferably, a mixture of (XI) and either (XA) or (XB) is treated with about one molecular equivalent of the coupling reagent (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) in a suitable solvent such as dimethylformamide at about room temperature.
In a further variation, the carboxylic acid function of (XI) may first of all be activated using up to about a 5% excess of a reagent such as N,Nxe2x80x2-carbonyldiimidazole in a suitable solvent, e.g. ethyl acetate or butan-2-one, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with either (XA) or (XB) at from about 20 to about 90xc2x0 C.
The amines of formula (III), the 4-aminopyrazole-5-carboxamides of formulae (VII), (XA) and (XB), the carboxylic acid derivatives of formula (VIII) and the carboxylic acids of formula (XI), when neither commercially available nor subsequently described, can be obtained either by analogy with the processes described in the Preparations section or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described hereinafter in the Examples and Preparations sections which allow the compounds defined by formulae (IA) and (IB) to be obtained.
The pharmaceutically acceptable acid addition salts of the compounds of formulae (IA) and (IB) which contain a basic centre may also be prepared in a conventional manner. For example a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (IA) or (IB) with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The biological activities of the compounds of the present invention were determined by the following test methods.
In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases were determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina.
Assays were performed using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228). Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
This was assessed in vitro by determining the capactiy of a compound of the invention to enhance sodium nitroprusside-induced relaxation of pre-contracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (suppl.), abstract 153P).
Compounds were screened in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
In human therapy, the compounds of formulae (IA) and (IB), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity, can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Preferably, they are administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
For oral, parenteral, buccal and sublingual administration to patients, the daily dosage level of the compounds of formulae (IA) and (IB) and their pharmaceutically acceptable salts and solvates may be from 10 to 500 mg (in single or divided doses). Thus, for example, tablets or capsules may contain from 5 to 100 mg of active compound for administration singly, or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen in MED for a typical man is from 25 to 100 mg of compound when required. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, e.g. sublingually or buccally.
For veterinary use, a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus the invention provides a pharmaceutical composition comprising a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent or carrier.
It further provides a veterinary formulation comprising a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, together with a veterinarily acceptable diluent or carrier.
The invention also provides a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament.
In addition, it provides a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, or a veterinary formulation containing any of the foregoing, for use as an animal medicament.
In yet another aspect, the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated.
It also provides the use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated.
Moreover, the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate containing either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility.
It also provides the use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate containing either entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility.
Additionally, the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.
Still further, the invention provides a method of treating or preventing male erectile dysfunction, female sexual dysfunction, premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.
The invention also includes any novel intermediates described herein, for example those of formulae (IIA), (IIB), (IVA), (IVB), (IXA) and (IXB).
The syntheses of the compounds of the invention and of the intermediates for use therein are illustrated by the following Examples and Preparations.
1H Nuclear magnetic resonance (NMR) spectra were recorded using either a Varian Unity 300 or a Varian Inova 400 spectrometer and were in all cases consistent with the proposed structures. Characteristic chemical shifts (xcex4) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.
Mass spectra (m/z) were recorded using a Fisons Instruments Trio mass spectrometer in the thermospray ionisation mode.
Room temperature means 20 to 25xc2x0 C.